Marijuana (cannabis sativa) use during adolescence normally predates the use of "heavy" drugs such as heroin in later life, which has raised speculations as to possible "gateway" effects of marijuana. Factors such as drug-associated environment and inherent individual differences (e.g., impulsivity, hyperactivity), which predates early drug use and can influence neurodevelopment during adolescence, appear to increase the risk for substance abuse disorders. The mesocorticolimbic system (MCLS) is critically involved in, e.g., emotional regulation, reward, and motivation and express significant levels of cannabinoid receptors (CB1). We have observed that cannabis-exposed human fetuses have impaired dopamine (DA)-related gene expression in the amygdala, a component of the MCLS (which also includes the nucleus accumbens (NAcc), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC)). Moreover, we found that adolescent rats administered THC (the psychoactive component of cannabis) have increased heroin intake in adulthood suggesting a link between the cannabinoid and opioid systems. It is the goal of this proposal to identify neurobiological alterations in MCLS structures that can account for the effects of THC exposure during adolescence on heroin self-administration in adulthood. In vivo DA levels as well as gene expression and receptor binding linked to the CB1, opioid neuropeptides, and DA neural systems will be studied in MCLS structures in adult rats exposed to THC during adolescence. The impact of risk factors such as behavioral individual differences (e.g., high behavioral activity, high impulsivity) and the environmental context of THC exposure will also be evaluated in regard to their influence on heroin self-administration behavior and neurobiology. These studies should provide information as to whether there exist a long-term impact of THC exposure during development to substantiate a neurobiological "gateway" hypothesis and, if so, help to identify potential risk factors in adolescents that can influence the risk for heroin abuse in adulthood.